A wealth of experimental and clinical data demonstrates that the complement system is involved in the pathogenesis of numerous inflammatory diseases. Complement activation contributes to injury in disorders that involve nearly every tissue in the body. Concerted effort has been expended in recent years to develop therapeutic complement inhibitors. Eculizumab, an inhibitory antibody to C5, was recently approved for the treatment of several diseases, and many other complement inhibitors are in clinical development. As these drugs are developed, the need for improved methods of detecting and monitoring complement activation within particular tissues will be increasingly important. We have developed a magnetic resonance imaging (MRI)-based method for noninvasive detection of complement activation. This method utilizes iron-oxide nanoparticles that are targeted to sites of complement activation with a recombinant protein that contains the C3d-binding region of complement receptor (CR) 2. Iron-oxide nanoparticles darken (negatively enhance) images obtained by T2-weighted MRI. We have demonstrated that the CR2-targeted nanoparticles bind within the kidneys of mice with lupus-like kidney disease (MRL/1pr mice), causing a decrease in the T2 signal within the kidneys. This method discriminates diseased kidneys from healthy controls, and the magnitude of the negative enhancement in the cortex of MRL/lpr mice correlates with their disease severity. This method may be useful for identifying those patients most likely to benefit from complement inhibitors and for monitoring the response of these patients to treatment. These results may open up new avenues to develop tools for the monitoring of disease progression in complement-dependent diseases.